CD81

Gene Summary

Gene:CD81; CD81 molecule
Aliases: S5.7, CVID6, TAPA1, TSPAN28
Location:11p15.5
Summary:The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins. This protein appears to promote muscle cell fusion and support myotube maintenance. Also it may be involved in signal transduction. This gene is localized in the tumor-suppressor gene region and thus it is a candidate gene for malignancies. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:CD81 antigen
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD81 (cancer-related)

Hong IK, Byun HJ, Lee J, et al.
The tetraspanin CD81 protein increases melanoma cell motility by up-regulating metalloproteinase MT1-MMP expression through the pro-oncogenic Akt-dependent Sp1 activation signaling pathways.
J Biol Chem. 2014; 289(22):15691-704 [PubMed] Article available free on PMC after 30/05/2015 Related Publications
Despite the importance of multiple tetraspanin proteins in cancer invasion and metastasis, little is known about the role and significance of tetraspanin CD81 in these processes. In the present study, we examined CD81 effects on melanoma cell invasiveness and metastasis. Transfection of CD81 into melanoma cells lacking endogenous CD81 expression significantly enhanced the migrating, invasive, and metastatic abilities of melanoma cells. Interestingly, membrane type 1 matrix metalloproteinase (MT1-MMP) expression was found in CD81-expressing melanoma cells but not in CD81-deficient cells. siRNA knockdown of CD81 in melanoma cells with endogenous CD81 demonstrated decreased MT1-MMP levels and cell motility. Notably, CD81-induced cell migration was abrogated by antibody blocking and siRNA knockdown of MT1-MMP, indicating that MT1-MMP is responsible for CD81-stimulated melanoma cell migration. Promoter analysis revealed an essential role of the Sp1 transcription factor in CD81-induced MT1-MMP transcription. We also demonstrate that the Sp1-activating Akt pathway is involved in adhesion-dependent CD81 signaling to induce MT1-MMP expression and cell motility. Importantly, human skin cancer tissue specimens displayed a positive correlation of CD81 with MT1-MMP expression levels and a close association of CD81 with malignant melanomas. Taken together, these results strongly suggest that CD81 stimulates melanoma cell motility by inducing MT1-MMP expression through the Akt-dependent Sp1 activation signaling pathway, leading to increased melanoma invasion and metastasis.

Martínez R, Carmona FJ, Vizoso M, et al.
DNA methylation alterations in grade II- and anaplastic pleomorphic xanthoastrocytoma.
BMC Cancer. 2014; 14:213 [PubMed] Article available free on PMC after 30/05/2015 Related Publications
BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is a rare WHO grade II tumor accounting for less than 1% of all astrocytomas. Malignant transformation into PXA with anaplastic features, is unusual and correlates with poorer outcome of the patients.
METHODS: Using a DNA methylation custom array, we have quantified the DNA methylation level on the promoter sequence of 807 cancer-related genes of WHO grade II (n = 11) and III PXA (n = 2) and compared to normal brain tissue (n = 10) and glioblastoma (n = 87) samples. DNA methylation levels were further confirmed on independent samples by pyrosequencing of the promoter sequences.
RESULTS: Increasing DNA promoter hypermethylation events were observed in anaplastic PXA as compared with grade II samples. We further validated differential hypermethylation of CD81, HCK, HOXA5, ASCL2 and TES on anaplastic PXA and grade II tumors. Moreover, these epigenetic alterations overlap those described in glioblastoma patients, suggesting common mechanisms of tumorigenesis.
CONCLUSIONS: Even taking into consideration the small size of our patient populations, our data strongly suggest that epigenome-wide profiling of PXA is a valuable tool to identify methylated genes, which may play a role in the malignant progression of PXA. These methylation alterations may provide useful biomarkers for decision-making in those patients with low-grade PXA displaying a high risk of malignant transformation.

Tembhare PR, Yuan CM, Venzon D, et al.
Flow cytometric differentiation of abnormal and normal plasma cells in the bone marrow in patients with multiple myeloma and its precursor diseases.
Leuk Res. 2014; 38(3):371-6 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognostication of plasma cell dyscrasias (PCD) is challenging. We studied antigen expression in normal plasma cells (NPC) (N = 34) and APC in a series of unselected PCD (N = 59). NPC subpopulations often demonstrated CD19(-), CD20(+), CD45(-) or dim and CD56(+), an immunophenotype observed in PCD. However abnormal CD81 was only observed in APCs (APC detection sensitivity 95%; specificity 100%). We evaluated differences in antigen expression patterns among MGUS (N = 14), SMM (N = 35) and MM (N = 10), finding the combination of CD45 and CD56 helpful in differentiating MGUS from SMM and MM (p = 0.0002).

Zhang HG, Grizzle WE
Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions.
Am J Pathol. 2014; 184(1):28-41 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Normal and diseased cells release bilayered membrane-bound nanovesicles into interstitial spaces and into bodily fluids. A subgroup of such microvesicles is called exosomes and is described in blood as 30 to 100 nm in diameter and as spherical to cup-shaped nanoparticles with specific surface molecular characteristics (eg, expression of the tetraspanins CD9, CD81, and CD63). Extracellular microvesicles provide local signals (eg, autocrine and paracrine) and distant endocrine signals to cells via the transfer of their contents, which include signal proteins, lipids, miRNAs, and functional mRNAs. Exosomes and related microvesicles also aid cells in exporting less-needed molecules and potentially harmful molecules, including drugs; in the case of neoplasia, the export of chemotherapeutic drugs may facilitate cellular chemoresistance. Cancers have adapted the exosome and related microvesicles as a pathway by which neoplastic cells communicate with each other (autocrine) and with nonneoplastic cells (paracrine and endocrine); via this pathway, cancer suppresses the immune system and establishes a fertile local and distant environment to support neoplastic growth, invasion, and metastases. Because exosomes mirror and bind to the cells from which they arise, they can be used for delivery of drugs, vaccines, and gene therapy, as biomarkers and targets. We review how exosomes and related extracellular microvesicles facilitate the progression and metastases of cancers and describe how these microvesicles may affect clinical care.

Gustafson-Wagner E, Stipp CS
The CD9/CD81 tetraspanin complex and tetraspanin CD151 regulate α3β1 integrin-dependent tumor cell behaviors by overlapping but distinct mechanisms.
PLoS One. 2013; 8(4):e61834 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Integrin α3β1 potently promotes cell motility on its ligands, laminin-332 and laminin-511, and this may help to explain why α3β1 has repeatedly been linked to breast carcinoma progression and metastasis. The pro-migratory functions of α3β1 depend strongly on lateral interactions with cell surface tetraspanin proteins. Tetraspanin CD151 interacts directly with the α3 integrin subunit and links α3β1 integrin to other tetraspanins, including CD9 and CD81. Loss of CD151 disrupts α3β1 association with other tetraspanins and impairs α3β1-dependent motility. However, the extent to which tetraspanins other than CD151 are required for specific α3β1 functions is unclear. To begin to clarify which aspects of α3β1 function require which tetraspanins, we created breast carcinoma cells depleted of both CD9 and CD81 by RNA interference. Silencing both of these closely related tetraspanins was required to uncover their contributions to α3β1 function. We then directly compared our CD9/CD81-silenced cells to CD151-silenced cells. Both CD9/CD81-silenced cells and CD151-silenced cells showed delayed α3β1-dependent cell spreading on laminin-332. Surprisingly, however, once fully spread, CD9/CD81-silenced cells, but not CD151-silenced cells, displayed impaired α3β1-dependent directed motility and altered front-rear cell morphology. Also unexpectedly, the CD9/CD81 complex, but not CD151, was required to promote α3β1 association with PKCα in breast carcinoma cells, and a PKC inhibitor mimicked aspects of the CD9/CD81-silenced cell motility defect. Our data reveal overlapping, but surprisingly distinct contributions of specific tetraspanins to α3β1 integrin function. Importantly, some of CD9/CD81's α3β1 regulatory functions may not require CD9/CD81 to be physically linked to α3β1 by CD151.

Andrew AS, Hu T, Gu J, et al.
HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.
PLoS One. 2012; 7(12):e51301 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Bladder cancer is the 4(th) most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25) than females (OR 1.56 95%CI 0.83-2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.

Yoo TH, Ryu BK, Lee MG, Chi SG
CD81 is a candidate tumor suppressor gene in human gastric cancer.
Cell Oncol (Dordr). 2013; 36(2):141-53 [PubMed] Related Publications
BACKGROUND: CD81 is a transmembrane protein that serves as a putative receptor for hepatitis C virus. In addition, CD81 has been suggested to be involved in a broad range of other cellular functions. Its putative implication in tumorigenesis has so far, however, remained largely unexplored. To assess the candidacy of CD81 as a tumor suppressor in gastric cancer development, we investigated its expression and function in a series of primary gastric tumors and gastric tumor-derived cell lines.
METHODS: The expression and concomitant methylation status of the CD81 gene and its effect on tumor development and cellular signaling were evaluated.
RESULTS: CD81 mRNA levels were found to be low in 16 of 40 (40 %) primary tumors and 9 of 14 (64.2 %) cell lines, and these low expression levels were found to correlate with the stage and grade of the tumors. Genomic alterations of CD81 were not encountered, whereas its expression could be re-activated in low expressing cells upon 5-aza-dC treatment. Bisulfite DNA sequencing analysis of 10 CpG sites within the 5' proximal region of the CD81 gene promoter revealed that the observed transcriptional silencing was tightly associated with aberrant hypermethylation. Subsequent restoration of CD81 expression induced a G1 cell cycle arrest and apoptosis, whereas siRNA-mediated CD81 down-regulation promoted cell proliferation and attenuated cellular responses to various apoptotic stress stimuli. Also the colony-forming ability of the tumor cells could be inhibited and enhanced through CD81 up- and down-regulation, respectively. CD81 was found to inhibit p38 (but not ERK, JNK and AKT) phosphorylation and its growth suppressive effect could be abolished through p38 up- and down-regulation.
CONCLUSION: From our data we conclude that epigenetic inactivation of CD81 is a common feature of gastric tumors and that this inactivation may render growth and survival advantages to the tumor cells, at least partially through p38 signaling.

Yoshio S, Kanto T, Kuroda S, et al.
Human blood dendritic cell antigen 3 (BDCA3)(+) dendritic cells are a potent producer of interferon-λ in response to hepatitis C virus.
Hepatology. 2013; 57(5):1705-15 [PubMed] Related Publications
UNLABELLED: The polymorphisms in the interleukin (IL)-28B (interferon-lambda [IFN]-λ3) gene are strongly associated with the efficacy of hepatitis C virus (HCV) clearance. Dendritic cells (DCs) sense HCV and produce IFNs, thereby playing some cooperative roles with HCV-infected hepatocytes in the induction of interferon-stimulated genes (ISGs). Blood dendritic cell antigen 3 (BDCA3)(+) DCs were discovered as a producer of IFN-λ upon Toll-like receptor 3 (TLR3) stimulation. We thus aimed to clarify the roles of BDCA3(+) DCs in anti-HCV innate immunity. Seventy healthy subjects and 20 patients with liver tumors were enrolled. BDCA3(+) DCs, in comparison with plasmacytoid DCs and myeloid DCs, were stimulated with TLR agonists, cell-cultured HCV (HCVcc), or Huh7.5.1 cells transfected with HCV/JFH-1. BDCA3(+) DCs were treated with anti-CD81 antibody, inhibitors of endosome acidification, TIR-domain-containing adapter-inducing interferon-β (TRIF)-specific inhibitor, or ultraviolet-irradiated HCVcc. The amounts of IL-29/IFN-λ1, IL-28A/IFN-λ2, and IL-28B were quantified by subtype-specific enzyme-linked immunosorbent assay (ELISA). The frequency of BDCA3(+) DCs in peripheral blood mononuclear cell (PBMC) was extremely low but higher in the liver. BDCA3(+) DCs recovered from PBMC or the liver released large amounts of IFN-λs, when stimulated with HCVcc or HCV-transfected Huh7.5.1. BDCA3(+) DCs were able to induce ISGs in the coexisting JFH-1-positive Huh7.5.1 cells. The treatments of BDCA3(+) DCs with anti-CD81 antibody, cloroquine, or bafilomycin A1 reduced HCVcc-induced IL-28B release, whereas BDCA3(+) DCs comparably produced IL-28B upon replication-defective HCVcc. The TRIF-specific inhibitor reduced IL-28B release from HCVcc-stimulated BDCA3(+) DCs. In response to HCVcc or JFH-1-Huh7.5.1, BDCA3(+) DCs in healthy subjects with IL-28B major (rs8099917, TT) released more IL-28B than those with IL-28B minor genotype (TG).
CONCLUSION: Human BDCA3(+) DCs, having a tendency to accumulate in the liver, recognize HCV in a CD81-, endosome-, and TRIF-dependent manner and produce substantial amounts of IL-28B/IFN-λ3, the ability of which is superior in subjects with IL-28B major genotype.

Chiba M, Kimura M, Asari S
Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines.
Oncol Rep. 2012; 28(5):1551-8 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Exosomes are microvesicles that are released from various cells into the extracellular space. It has been reported that the components within exosomes vary according to the type of secreted cell. In the present study, we investigated the tetraspanin family proteins CD63, CD9 and CD81 as useful collection markers of exosomes derived from the three colorectal cancer (CRC) cell lines HCT-15, SW480 and WiDr. In addition, we aimed to detect the mRNAs, microRNAs and natural antisense RNAs within the exosomes secreted from the three CRC cell lines. Furthermore, we examined whether exosomes containing their RNAs were transferred into the hepatoma cell line HepG2 and lung cancer cell line A549. CD81 was detected in exosomes secreted from the three CRC cell lines. This result indicates that CD81 can be a collection marker of exosomes derived from the three CRC cell lines. When the RNA species within exosomes derived from the three CRC cell lines were examined, the mRNAs of housekeeping genes such as ACTB and GAPDH, the microRNAs such as miR-21, miR-192 and miR-221, and the natural antisense RNAs of LRRC24, MDM2 and CDKN1A genes, were detected. We discovered their natural antisense RNAs within exosomes for the first time in the present study. Furthermore, PKH67-labeled exosomes derived from the CRC cell lines were taken up into HepG2 and A549 cells. These findings indicate that the intracellular RNAs enclosed within exosomes are secreted to the outside, and exosomes derived from the CRC cell lines are transferred into HepG2 and A549 cells. In conclusion, we reveal that exosomes derived from the CRC cell lines contain mRNAs, microRNAs and natural antisense RNAs, and can be delivered into HepG2 and A549 cells. These findings indicate that exosomal RNAs can shuttle between cells, and may be involved in the regulation of gene expression in recipient cells.

Skiriute D, Vaitkiene P, Saferis V, et al.
MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma.
BMC Cancer. 2012; 12:218 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Methylation of promoter region is the major mechanism affecting gene expression in tumors. Recent methylome studies of brain tumors revealed a list of new epigenetically modified genes. Our aim was to study promoter methylation of newly identified epigenetically silenced genes together with already known epigenetic markers and evaluate its separate and concomitant role in glioblastoma genesis and patient outcome.
METHODS: The methylation status of MGMT, CD81, GATA6, DR4, and CASP8 in 76 patients with primary glioblastomas was investigated. Methylation-specific PCR reaction was performed using bisulfite treated DNA. Evaluating glioblastoma patient survival time after operation, patient data and gene methylation effect on survival was estimated using survival analysis.
RESULTS: The overwhelming majority (97.3%) of tumors were methylated in at least one of five genes tested. In glioblastoma specimens gene methylation was observed as follows: MGMT in 51.3%, GATA6 in 68.4%, CD81 in 46.1%, DR4 in 41.3% and CASP8 in 56.8% of tumors. Methylation of MGMT was associated with younger patient age (p < 0.05), while CASP8 with older (p < 0.01). MGMT methylation was significantly more frequent event in patient group who survived longer than 36 months after operation (p < 0.05), while methylation of CASP8 was more frequent in patients who survived shorter than 36 months (p < 0.05). Cox regression analysis showed patient age, treatment, MGMT, GATA6 and CASP8 as independent predictors for glioblastoma patient outcome (p < 0.05). MGMT and GATA6 were independent predictors for patient survival in younger patients' group, while there were no significant associations observed in older patients' group when adjusted for therapy.
CONCLUSIONS: High methylation frequency of tested genes shows heterogeneity of glioblastoma epigenome and the importance of MGMT, GATA6 and CASP8 genes methylation in glioblastoma patient outcome.

Paiva B, Gutiérrez NC, Chen X, et al.
Clinical significance of CD81 expression by clonal plasma cells in high-risk smoldering and symptomatic multiple myeloma patients.
Leukemia. 2012; 26(8):1862-9 [PubMed] Related Publications
The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81(+) SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma.

Esser R, Glienke W, Bochennek K, et al.
Detection of neuroblastoma cells during clinical follow up: advanced flow cytometry and rt-PCR for tyrosine hydroxylase using both conventional and real-time PCR.
Klin Padiatr. 2011; 223(6):326-31 [PubMed] Related Publications
PURPOSE: Real-time reverse-transcriptase PCR (RT-qPCR) or conventional RT-PCR (RT-cPCR) detection of tyrosine hydroxylase (TH) is increasingly used to detect neuroblastoma (NB) cells in clinical samples. However, TH expression in normal tissues can limit its usefulness and make additional diagnostic strategies necessary.
METHODS: We analysed TH in 857 tumour, bone marrow aspirate and peripheral blood stem cell samples from 65 NB patients using RT-cPCR, and compared results from 666 samples analysed by RT-qPCR. TH was investigated in 84 samples from patients with other diagnoses and 354 samples from healthy donors as controls, and 132 samples from the entire collection were evaluated for NB cells using 5-colour flow cytometry (FC).
RESULTS: Cohen's kappa coefficient demonstrated a substantial agreement between RT-cPCR and RT-qPCR as well as RT-cPCR and FC and a moderate agreement between RT-qPCR and FC. TH expression was also detected in samples from individual patients with Ewing sarcoma, nephroblastoma and rhabdomyosarcoma, but not from healthy donors. FC panels were an effective complementary strategy, detecting as few as 0.002% NB cells, characterised as CD45negCD9+CD81+CD56+ch14:18+GD2+ cells with occasional CD57+CD138+CD166+ expression.
CONCLUSION: TH RT-qPCR alone is limited for detection of NB cells because of "false positives" in samples from patients with other diseases. Advanced FC may serve as a complementary method to detect residual NB, but needs further confirmation in larger patient cohorts.

Nicolau A, Tănăsescu R, Bălănescu E, et al.
Hepatitis C virus-mixed cryoglobulinemia-lymphoma relationship.
Rom J Intern Med. 2011; 49(1):3-10 [PubMed] Related Publications
HCV (hepatitis C virus) chronic hepatitis has become one the most expensive diseases for public health systems all over the world in the past 10-20 years, a real epidemic, the second most frequent, after hepatitis B virus infection. Due to the complex manifestations, one may consider HCV infection as a "systemic" disease. Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of HCV infection, but cryoglobulinemic vasculitis (CV) is considered to be relatively sparse although prevalence studies are needed. Presence of serum cryoglobulins is essential for MC diagnosis, but serum levels do not correlate with the disease activity or prognosis. MC can be defined as a B lymphocyte proliferation disease being characterized by polyclonal activation and antibody synthesis. Evolution to lymphoma should be considered continuous but also other infectious, environmental or genetic factors could be involved. The t (14.18) translocation and Bcl-2 activation in B lymphocytes, B cell-activating factor (BAFF), E2-CD81 interaction, immunoregulatory T CD4+CD25(high) + lymphocytes and type III IFNs might play an important role in MC and lymphoma evolution in HCV patients.

Colin S, Guilmain W, Creoff E, et al.
A truncated form of CD9-partner 1 (CD9P-1), GS-168AT2, potently inhibits in vivo tumour-induced angiogenesis and tumour growth.
Br J Cancer. 2011; 105(7):1002-11 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Tetraspanins are transmembrane proteins known to contribute to angiogenesis. CD9 partner-1 (CD9P-1/EWI-F), a glycosylated type 1 transmembrane immunoglobulin, is a member of the tetraspanin web, but its role in angiogenesis remains to be elucidated.
METHODS: We measured the expression of CD9P-1 under angiogenic and angiostatic conditions, and the influence of its knockdown onto capillary structures formation by human endothelial cells (hECs). A truncated form of CDP-1, GS-168AT2, was produced and challenged vs hEC proliferation, migration and capillaries' formation. Its association with CD9P-1, CD9, CD81 and CD151 and the expressions of these later at hEC surface were analysed. Finally, its effects onto in vivo tumour-induced angiogenesis and tumour growth were investigated.
RESULTS: Vascular endothelial growth factor (VEGF)-induced capillary tube-like formation was inhibited by tumour necrosis factor α and was associated with a rise in CD9P-1 mRNA expression (P<0.05); accordingly, knockdown of CD9P-1 inhibited VEGF-dependent in vitro angiogenesis. GS-168AT2 dose-dependently inhibited in vitro angiogenesis, hEC migration and proliferation (P<0.05). Co-precipitation experiments suggest that GS-168AT2 corresponds to the sequence by which CD9P-1 physiologically associates with CD81. GS-168AT2 induced the depletion of CD151, CD9 and CD9P-1 from hEC surface, correlating with GS-168AT2 degradation. Finally, in vivo injections of GS-168AT2 inhibited tumour-associated angiogenesis by 53.4±9.5% (P=0.03), and reduced tumour growth of Calu 6 tumour xenografts by 73.9±16.4% (P=0.007) without bodyweight loss.
CONCLUSION: The truncated form of CD9P-1, GS-168AT2, potently inhibits angiogenesis and cell migration by at least the downregulation of CD151 and CD9, which provides the first evidences for the central role of CD9P-1 in tumour-associated angiogenesis and tumour growth.

Long G, Hiet MS, Windisch MP, et al.
Mouse hepatic cells support assembly of infectious hepatitis C virus particles.
Gastroenterology. 2011; 141(3):1057-66 [PubMed] Related Publications
BACKGROUND & AIMS: Hepatitis C virus (HCV) has a high propensity to establish persistence; better understanding of this process requires the development of a fully permissive and immunocompetent small animal model. Mouse cells can be engineered to express the human orthologs of the entry molecules CD81 and occludin to allow entry of HCV. However, RNA replication is poor in mouse cells, and it is not clear whether they support assembly and release of infectious HCV particles. We used a trans-complementation-based system to demonstrate HCV assembly competence of mouse liver cell lines.
METHODS: A panel of 3 mouse hepatoma cell lines that contain a stable subgenomic HCV replicon was used for ectopic expression of the HCV structural proteins, p7, nonstructural protein 2, and/or apolipoprotein E (apoE). Assembly and release of infectious HCV particles was determined by measuring viral RNA, proteins, and infectivity of virus released into the culture supernatant.
RESULTS: Mouse replicon cells released low amounts of HCV particles, but ectopic expression of apoE increased release of infectious HCV to levels observed in the human hepatoma cell line Huh7.5. Thus, apoE is the limiting factor for assembly of HCV in mouse hepatoma cells but probably not in primary mouse hepatocytes. Products of all 3 human alleles of apoE and mouse apoE support HCV assembly with comparable efficiency. Mouse and human cell-derived HCV particles have similar biophysical properties, dependency on entry factors, and levels of association with apoE.
CONCLUSIONS: Mouse hepatic cells permit HCV assembly and might be developed to create an immunocompetent and fully permissive mouse model of HCV infection.

Olkhanud PB, Damdinsuren B, Bodogai M, et al.
Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells.
Cancer Res. 2011; 71(10):3505-15 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Pulmonary metastasis of breast cancer requires recruitment and expansion of T-regulatory cells (Treg) that promote escape from host protective immune cells. However, it remains unclear precisely how tumors recruit Tregs to support metastatic growth. Here we report the mechanistic involvement of a unique and previously undescribed subset of regulatory B cells. These cells, designated tumor-evoked Bregs (tBreg), phenotypically resemble activated but poorly proliferative mature B2 cells (CD19(+) CD25(High) CD69(High)) that express constitutively active Stat3 and B7-H1(High) CD81(High) CD86(High) CD62L(Low) IgM(Int). Our studies with the mouse 4T1 model of breast cancer indicate that the primary role of tBregs in lung metastases is to induce TGF-β-dependent conversion of FoxP3(+) Tregs from resting CD4(+) T cells. In the absence of tBregs, 4T1 tumors cannot metastasize into the lungs efficiently due to poor Treg conversion. Our findings have important clinical implications, as they suggest that tBregs must be controlled to interrupt the initiation of a key cancer-induced immunosuppressive event that is critical to support cancer metastasis.

Guilmain W, Colin S, Legrand E, et al.
CD9P-1 expression correlates with the metastatic status of lung cancer, and a truncated form of CD9P-1, GS-168AT2, inhibits in vivo tumour growth.
Br J Cancer. 2011; 104(3):496-504 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Loss of CD9 expression has been correlated with a higher motility and metastatic potential of tumour cells originating from different organs. However, the mechanism underlying this loss is not yet understood.
METHODS: We produced a truncated form of partner 1 of CD9 (CD9P-1), GS-168AT2, and developed a new monoclonal antibody directed towards the latter. We measured the expression of CD9 and CD9P-1 in human lung tumours (hLTs), and monitored the level of CD9 in NCI-H460, in vitro and in vivo, in the presence and absence of GS-168AT2.
RESULTS: Loss of CD9 is inversely related to the expression of CD9P-1, which correlates with the metastatic status of hLT (n=55). In vitro, GS-168AT2 is rapidly internalised and degraded at both the membrane and cytoplasm of NCI-H460, and this correlates with the association of GS-168AT2 with both CD9 and CD81. Intraperitoneal injections of GS-168AT2 in NCI-H460-xenografted Nude mice led to drastic inhibition of tumour growth, as well as to the downregulation of CD9, but not of CD81, in the tumour core.
CONCLUSION: These findings show for the first time that CD9P-1 expression positively correlates with the metastatic status of hLT, and that the upregulation of CD9P-1 expression could be one of the mechanisms underlying the loss of CD9 in solid tumours. Our study also reveals that, under certain conditions, loss of CD9 could be a tumour growth-limiting phenomenon rather than a tumour growth-promoting one.

Eyre NS, Drummer HE, Beard MR
The SR-BI partner PDZK1 facilitates hepatitis C virus entry.
PLoS Pathog. 2010; 6(10):e1001130 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Entry of hepatitis C virus (HCV) into hepatocytes is a multi-step process that involves a number of different host cell factors. Following initial engagement with glycosaminoglycans and the low-density lipoprotein receptor, it is thought that HCV entry proceeds via interactions with the tetraspanin CD81, scavenger receptor class B type I (SR-BI), and the tight-junction proteins claudin-1 (CLDN1) and occludin (OCLN), culminating in clathrin-dependent endocytosis of HCV particles and their pH-dependent fusion with endosomal membranes. Physiologically, SR-BI is the major receptor for high-density lipoproteins (HDL) in the liver, where its expression is primarily controlled at the post-transcriptional level by its interaction with the scaffold protein PDZK1. However, the importance of interaction with PDZK1 to the involvement of SR-BI in HCV entry is unclear. Here we demonstrate that stable shRNA-knockdown of PDZK1 expression in human hepatoma cells significantly reduces their susceptibility to HCV infection, and that this effect can be reversed by overexpression of full length PDZK1 but not the first PDZ domain of PDZK1 alone. Furthermore, we found that overexpression of a green fluorescent protein chimera of the cytoplasmic carboxy-terminus of SR-BI (amino acids 479-509) in Huh-7 cells resulted in its interaction with PDZK1 and a reduced susceptibility to HCV infection. In contrast a similar chimera lacking the final amino acid of SR-BI (amino acids 479-508) failed to interact with PDZK1 and did not inhibit HCV infection. Taken together these results indicate an indirect involvement of PDZK1 in HCV entry via its ability to interact with SR-BI and enhance its activity as an HCV entry factor.

Banaudha K, Orenstein JM, Korolnek T, et al.
Primary hepatocyte culture supports hepatitis C virus replication: a model for infection-associated hepatocarcinogenesis.
Hepatology. 2010; 51(6):1922-32 [PubMed] Related Publications
UNLABELLED: Analysis of progressive changes in hepatic gene expression that underlie hepatocarcinogenesis following hepatitis C virus (HCV) infection require examination of long-term cultures of normally differentiating primary human hepatocytes. We report a culture system of primary hepatocytes that support productive replication of infectious HCV. Hepatic functions were analyzed by reverse-transcription polymerase chain reaction amplification of total cell RNA from cultures maintained in serum-free defined medium for up to 190 days. Sustained hepatic function was assessed by expression of albumin, alpha-fetoprotein, cytochrome P4502E1, cytokeratin-18, type-1 collagen, transforming growth factor-beta 1, matrix metalloproteinase-2 (MMP-2), MMP-13, and interferon alpha-receptors 1 and 2. Normally differentiated human primary hepatocytes supported productive replication of infectious clones of HCV genotypes 1a, 1b, and 2a; virus infection was inhibited by antibodies against CD81 virus entry factor. Virus released into the culture media of HCV-infected primary hepatocytes repeatedly passage to naïve hepatocytes. Replication of the three HCV genotypes shows interferon sensitivity observed in natural infections.
CONCLUSION: Sustained cultures of physiologic host cells for the propagation of infectious HCV strains should accelerate studies of host response to HCV infection and progressive liver disease.

Dunn CD, Sulis ML, Ferrando AA, Greenwald I
A conserved tetraspanin subfamily promotes Notch signaling in Caenorhabditis elegans and in human cells.
Proc Natl Acad Sci U S A. 2010; 107(13):5907-12 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
The cytosolic domain of Notch is a membrane-tethered transcription factor. Ligand binding ultimately leads to gamma-secretase cleavage within the transmembrane domain, allowing the intracellular domain to translocate to the nucleus and activate target gene transcription. Constitutive Notch signaling has been associated with human cancers such as T cell acute lymphoblastic leukemia (T-ALL). As tetraspanins have been implicated in many different signaling processes, we assessed their potential contribution to Notch signaling. We used a genetic assay in Caenorhabditis elegans to identify TSP-12 as a positive factor for Notch activity in several cellular contexts. Then, using a cell culture system, we showed that two human TSP-12 orthologs, TSPAN33 and TSPAN5, promote Notch activity and are likely to act at the gamma-secretase cleavage step. We also acquired evidence for functional redundancy among tetraspanins in both C. elegans and human cells. Selective inhibition of tetraspanins may constitute an anti-NOTCH therapeutic approach to reduce gamma-secretase activity.

Xu L
GPR56 interacts with extracellular matrix and regulates cancer progression.
Adv Exp Med Biol. 2010; 706:98-108 [PubMed] Related Publications
GPR56 is a relatively recent addition to the adhesion-GPCR family. Genetic and biochemical studies uncovered its roles in cancer and development and established its function as an adhesion receptor to mediate the interactions between cells and extracellular matrix. Despite of much progress on understanding its biological implications, the mechanism of its function remains elusive. It has not been firmly established whether GPR56 signals directly through G proteins and what its upstream stimuli and downstream effectors are to execute its various biological effects. This chapter will give an overview of the primary structures of the Gpr56 gene and its encoded protein and attempt to point out open questions in this research area, with an emphasis on its roles in cancer and signal transduction.

Lv LP, Jia SZ, Wang QL, et al.
Hepatitis C virus infection of mouse hepatoma cell expressing human CD81 or LDLR.
Acta Virol. 2009; 53(3):185-9 [PubMed] Related Publications
Hepatitis C virus (HCV) infection represents a serious public health problem worldwide. Development of new therapeutics against HCV has been hampered by the lack of a small-animal model. Until now, it has been unclear which host factors influence the HCV infection. It was known that human CD81 (hCD81) or low-density lipoprotein receptor (hLDLR), the putative HCV receptors, induce concentration of viral particles on the cell surface. In this study, recombinant plasmids containing hCD81 or hLDLR genes were transfected to mouse hepatoma Hepa 1-6 cells and transgenic cell lines expressing hCD81 (hCD81/1-6 cell line) or hLDLR (hLDLR/1-6 cell line) on their surface have been established. HCV infection of these cell lines showed that the virus was bound, entered the cell, and replicated inside the cell. This finding is essential for the development of mouse model for the study of HCV replication in vivo.

Martinez R, Martin-Subero JI, Rohde V, et al.
A microarray-based DNA methylation study of glioblastoma multiforme.
Epigenetics. 2009; 4(4):255-64 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. The presence of epigenetic lesions, like hypermethylation of known tumor suppressor genes such as MGMT, has been widely described in GBM, but to our knowledge, a genome-wide profile of DNA methylation changes in these lethal tumors is not yet available. In the present analysis, we have quantified the DNA methylation level of 1,505 CpG dinucleotides (807 genes) in 87 consecutive GBMs using universal BeadArrays. Supervised cluster analyses identified 25 and seven genes that were respectively hypermethylated and hypomethylated in more than 20% of the cases studied. The most frequently hypermethylated genes were HOXA11, CD81, PRKCDBP, TES, MEST, TNFRSF10A and FZD9, being involved in more than half of the cases. Studying the biological features of hypermethylated genes, we found that the group of genes hypermethylated in GBM was highly enriched (41%, p < 0.001) for targets of the PRC2 (Polycomb repressive complex 2) in embryonic stem cells. This suggests that GBM might be derived from precursor cells with stem cell-like features. DNA methylation profiles were associated with overall survival in GBM, and we confirmed the favorable prognostic impact of MGMT methylation in patients treated with alkylating agents. Furthermore, we identified that promoter hypermethylation of the transcription factor gene GATA6 (occurring in 30% of GBM) was significantly associated with unfavorable patient survival.

Santamaria-Martínez A, Barquinero J, Barbosa-Desongles A, et al.
Identification of multipotent mesenchymal stromal cells in the reactive stroma of a prostate cancer xenograft by side population analysis.
Exp Cell Res. 2009; 315(17):3004-13 [PubMed] Related Publications
Cancer stem cells are a distinct cellular population that is believed to be responsible for tumor initiation and maintenance. Recent data suggest that solid tumors also contain another type of stem cells, the mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs), which contribute to the formation of tumor-associated stroma. The Hoechst 33342 efflux assay has proved useful to identify a rare cellular fraction, named Side Population (SP), enriched in cells with stem-like properties. Using this assay, we identified SP cells in a prostate cancer xenograft containing human prostate cancer cells and mouse stromal cells. The SP isolation, subculture and sequential sorting allowed the generation of single-cell-derived clones of murine origin that were recognized as MSC by their morphology, plastic adherence, proliferative potential, adipogenic and osteogenic differentiation ability and immunophenotype (CD45(-), CD81(+) and Sca-1(+)). We also demonstrated that SP clonal cells secrete transforming growth factor beta1 (TGF-beta1) and that their inhibition reduces proliferation and accelerates differentiation. These results reveal the existence of SP cells in the stroma of a cancer xenograft, and provide evidence supporting their MSC nature and the role of TGF-beta1 in maintaining their proliferation and undifferentiated status. Our data also reveal the usefulness of the SP assay to identify and isolate MSC cells from carcinomas.

Hirano C, Nagata M, Noman AA, et al.
Tetraspanin gene expression levels as potential biomarkers for malignancy of gingival squamous cell carcinoma.
Int J Cancer. 2009; 124(12):2911-6 [PubMed] Related Publications
Accurate assessment of malignancy in oral squamous cell carcinoma is essential to optimize treatment planning. To detect a biomarker related to malignant propensity in gingival squamous cell carcinoma (GSCC), quantitative gene expression analysis of tetraspanin family genes was conducted. In 73 cases of GSCC, total RNA was extracted from carcinoma tissues, and gene expression was analyzed by quantitative real time-PCR. Six tetraspanin family genes (CD9, CD63, CD81, CD82, CD151, NAG-2) were investigated. Housekeeping genes (ACTB and GAPDH), anchor protein genes (JUP and PXN) and an integrin gene (ITGA3) were used as reference genes. Forty-five gene expression ratios were calculated from these 11 gene expression levels and were analyzed with clinical parameters using multivariate statistical methods. According to the results of the logistic regression analysis subjecting cervical lymph node metastasis as a target variable, CD9/ACTB (p = 0.013) or CD9/CD82 (p = 0.013) in addition to tumor size (p = 0.028) were detected as significant factors. In Cox proportional hazards regression analysis, delayed cervical lymph node metastasis (p = 0.039) and tumor cell positive surgical margin (p = 0.032) in addition to CD151/GAPDH (p = 0.024) were detected as significant factors for death outcome. A Kaplan-Meier survival curve presented a significantly lower survival rate of the group with a CD151/GAPDH value of 10 or more (log rank and generalized Wilcoxon tests: p = 0.0003). Results of this study present the usefulness of CD9 and CD151 expression levels as biomarkers for assessment of malignancy in GSCC. They also indicate that detection of residual tumor cells at the surgical margin and the biological malignancy of a tumor interdependently affects prognosis.

Kolesnikova TV, Kazarov AR, Lemieux ME, et al.
Glioblastoma inhibition by cell surface immunoglobulin protein EWI-2, in vitro and in vivo.
Neoplasia. 2009; 11(1):77-86, 4p following 86 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
EWI-2, a cell surface IgSF protein, is highly expressed in normal human brain but is considerably diminished in glioblastoma tumors and cell lines. Moreover, loss of EWI-2 expression correlated with a shorter survival time in human glioma patients, suggesting that EWI-2 might be a natural inhibitor of glioblastoma. In support of this idea, EWI-2 expression significantly impaired both ectopic and orthotopic tumor growth in nude mice in vivo. In vitro assays provided clues regarding EWI-2 functions. Expression of EWI-2 in T98G and/or U87-MG malignant glioblastoma cell lines failed to alter two-dimensional cell proliferation but inhibited glioblastoma colony formation in soft agar and caused diminished cell motility and invasion. At the biochemical level, EWI-2 markedly affects the organization of four molecules (tetraspanin proteins CD9 and CD81 and matrix metalloproteinases MMP-2 and MT1-MMP), which play key roles in the biology of astrocytes and gliomas. EWI-2 causes CD9 and CD81 to become more associated with each other, whereas CD81 and other tetraspanins become less associated with MMP-2 and MT1-MMP. We propose that EWI-2 inhibition of glioblastoma growth in vivo is at least partly explained by the capability of EWI-2 to inhibit growth and/or invasion in vitro. Underlying these functional effects, EWI-2 causes a substantial molecular reorganization of multiple molecules (CD81, CD9, MMP-2, and MT1-MMP) known to affect proliferation and/or invasion of astrocytes and/or glioblastomas.

Farquhar MJ, Harris HJ, Diskar M, et al.
Protein kinase A-dependent step(s) in hepatitis C virus entry and infectivity.
J Virol. 2008; 82(17):8797-811 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Viruses exploit signaling pathways to their advantage during multiple stages of their life cycle. We demonstrate a role for protein kinase A (PKA) in the hepatitis C virus (HCV) life cycle. The inhibition of PKA with H89, cyclic AMP (cAMP) antagonists, or the protein kinase inhibitor peptide reduced HCV entry into Huh-7.5 hepatoma cells. Bioluminescence resonance energy transfer methodology allowed us to investigate the PKA isoform specificity of the cAMP antagonists in Huh-7.5 cells, suggesting a role for PKA type II in HCV internalization. Since viral entry is dependent on the host cell expression of CD81, scavenger receptor BI, and claudin-1 (CLDN1), we studied the role of PKA in regulating viral receptor localization by confocal imaging and fluorescence resonance energy transfer (FRET) analysis. Inhibiting PKA activity in Huh-7.5 cells induced a reorganization of CLDN1 from the plasma membrane to an intracellular vesicular location(s) and disrupted FRET between CLDN1 and CD81, demonstrating the importance of CLDN1 expression at the plasma membrane for viral receptor activity. Inhibiting PKA activity in Huh-7.5 cells reduced the infectivity of extracellular virus without modulating the level of cell-free HCV RNA, suggesting that particle secretion was not affected but that specific infectivity was reduced. Viral particles released from H89-treated cells displayed the same range of buoyant densities as did those from control cells, suggesting that viral protein association with lipoproteins is not regulated by PKA. HCV infection of Huh-7.5 cells increased cAMP levels and phosphorylated PKA substrates, supporting a model where infection activates PKA in a cAMP-dependent manner to promote virus release and transmission.

Li Y, Meng G, Guo QN
Changes in genomic imprinting and gene expression associated with transformation in a model of human osteosarcoma.
Exp Mol Pathol. 2008; 84(3):234-9 [PubMed] Related Publications
Genomic imprinting, a heritable form of epigenetic information, is thought to play an important role in tumor progression. DNA methylation is a common mechanism of genomic imprinting. To evaluate the genome-wide effects of malignant transformation on osteosarcoma progression, we examined multiple biological properties, including DNA methylation, in human osteoblast hFOB1.19 cells (ATCC Catalog No. CRL-11372) transformed by treatment with carcinogenic agent N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG, 1.0 microg/ml) and carcinogenic promoting agent 12-O-tetradecanoyl phorbol-13-acetate (TPA, 200 ng/ml). We also examined global changes in expression of imprinted genes during transformation using microarray analysis. Ten imprinted genes, including H19, MKRN3, NDN, CDKN1C, PHLDA2, MEST, CD81, GRB10, SLC22A18, and SLC22A3 were aberrantly regulated in transformed cells, suggesting roles in tumorigenesis. Moreover, we analyzed the methylation state of the promoter regions of H19, PHLDA2, and SLC22A18 genes by bisulfite sequencing array and observed a correlation between upregulated expression of H19 and PHLDA2 genes and hypomethylation of their promoter regions, although this was not observed for SLC22A18. Our results suggest that changes in expression of imprinted genes caused by changes in methylation are involved, and are among the earliest events, in neoplastic progression.

Mazzocca A, Liotta F, Carloni V
Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma.
Gastroenterology. 2008; 135(1):244-256.e1 [PubMed] Related Publications
BACKGROUND & AIMS: Human hepatocellular carcinoma (HCC) can invade the portal vein and metastasize to other parts of the liver. Currently, the molecular and cellular mechanisms underlying intrahepatic metastasis of HCC are poorly understood. Tumor invasiveness could be considered an aspect of dysregulated motility, and the mechanisms that inhibit cell movement are considered to counteract the spreading of cancer cells through the liver. Accumulating observations suggest that the CD81 tetraspanin may have an inhibitory effect on cell movement.
METHODS: In the present study using both loss- and gain-of-gene function approaches, we verified that the functional interaction of tetraspanin CD81 with type II phosphoinositide 4-kinase (PI4KII) suppressed HCC cell motility by promoting the formation of CD81-enriched vesicles, non-endosomal intracellular structures, that sequestered actinin-4 with consequent remodeling of actin cytoskeleton.
RESULTS: We reported that HCC cells expressing CD81 showed an inability to metastasize compared with HCC cells with undetectable levels of CD81.
CONCLUSIONS: Taken together, these findings indicate that CD81 functions as a molecular organizer of membrane microdomains, whereby proteins such as PI4KII control actin remodeling and cell motility, establishing a role for these genes as negative modifiers of oncogenicity and HCC progression.

Rawstron AC, Villamor N, Ritgen M, et al.
International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia.
Leukemia. 2007; 21(5):956-64 [PubMed] Related Publications
The eradication of minimal residual disease (MRD) in chronic lymphocytic leukaemia (CLL) predicts for improved outcome. However, the wide variety of MRD techniques makes it difficult to interpret and compare different clinical trials. Our aim was to develop a standardized flow cytometric CLL-MRD assay and compare it to real-time quantitative allele-specific oligonucleotide (RQ-ASO) Immunoglobulin heavy chain gene (IgH) polymerase chain reaction (PCR). Analysis of 728 paired blood and marrow samples demonstrated high concordance (87%) for patients off-therapy. Blood analysis was equally or more sensitive than marrow in 92% of samples but marrow analysis was necessary to detect MRD within 3 months of alemtuzumab therapy. Assessment of 50 CLL-specific antibody combinations identified three (CD5/CD19 with CD20/CD38, CD81/CD22 and CD79b/CD43) with low inter-laboratory variation and false-detection rates. Experienced operators demonstrated an accuracy of 95.7% (specificity 98.8%, sensitivity 91.1%) in 141 samples with 0.01-0.1% CLL. There was close correlation and 95% concordance with RQ-ASO IgH-PCR for detection of CLL above 0.01%. The proposed flow cytometry approach is applicable to all sample types and therapeutic regimes, and sufficiently rapid and sensitive to guide therapy to an MRD-negativity in real time. These techniques may be used as a tool for assessing response and comparing the efficacy of different therapeutic approaches.

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